Details

Autor(en) / Beteiligte

• Chigan, Jia‐Zhu
• Li, Jia‐Qi
• Ding, Huan‐Huan
• Xu, Yin‐Sui
• Liu, Lu
• Chen, Cheng
• Yang, Ke‐Wu

Titel

Hydroxamates as a potent skeleton for the development of metallo‐β‐lactamase inhibitors

Ist Teil von

• Chemical biology & drug design, 2022-02, Vol.99 (2), p.362-372

Ort / Verlag

England

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• Bacterial resistance caused by metallo‐β‐lactamases (MβLs) has become an emerging public health threat, and the development of MβLs inhibitor is an effective way to overcome the resistance. In this study, thirteen novel O‐aryloxycarbonyl hydroxamates were constructed and assayed against MβLs. The obtained molecules specifically inhibited imipenemase‐1 (IMP‐1) and New Delhi metallo‐β‐lactamase‐1, exhibiting an IC50 value in the range of 0.10–18.42 and 0.23–22.33 μM, respectively. The hydroxamate 5 was found to be the most potent inhibitor, with an IC50 of 0.1 and 0.23 μM using meropenem and cefazolin as substrates. ICP‐MS analysis showed that 5 did not coordinate to the Zn(II) ions at the active site of IMP‐1, while the rapid dilution, thermal shift and MALDI‐TOF assays revealed that the hydroxamate formed a covalent bond with the enzyme. Cytotoxicity assays indicated that the hydroxamates have low toxicity in MCF‐7 cells. This work provided a potent scaffold for the development of MβLs inhibitors. The hydroxamate derivatives exhibited potent and selective inhibition against metallo‐β‐lactamases IMP‐1 and NDM‐1 with IC50 values of 0.10 and 0.23 μM, and covalently and irreversibly bind to IMP‐1.